Drugs such as cocaine, methylphenidate and antidepressants that block monoamine transport are invariably nitrogen-based. The nitrogen is presumed to be necessary for anchoring the drug to the same aspartic acid residue on the transporter protein that bonds the nitrogen of a monoamine neurotransmitter. We developed a novel series of drugs which possess no nitrogen and bind to the dopamine, serotonin and norepinephrine transporters with relatively high affinity and various selectivities. In monkey striatum, a prototype compound bound to the dopamine transporter (IC50 10.5 + 1.5 nM) and blocked [3H]dopamine transport in cos-7 cells transiently expressing the human dopamine transporter cDNA (IC50 13 nM). This innovative series offers unique tools for modeling drug-transporter complexes and highlights the potential for developing a new generation of non-nitrogen containing drugs targeted to monoamine